Breast cancer is recognized as the most prevalent malignancy among women in North America with a life time risk currently estimated to be one in eight. Most importantly, reproductive history or more specifically steroid hormonal status has been shown to be an important risk factor. Recently, I generated a progesterone receptor (PR) knockout (PRKO) mouse that has demonstrated that progesterone (P), and its receptor, the PR, are absolutely required for normal mammary gland proliferation and differentiation. The involvement of P in mammary tumorigenesis has been a matter of controversy for several years mainly because P can protentiate or inhibit mammary tumorigenesis. To clarify the complex temporal relationship between P and mammary tumorigenesis, the PRKO mouse will be utilized to determine whether the P indued-proliferative signal has a role to play in breast cancer by investigating the effects of removing PR function on mammary tumor progression. The specific aims of this proposal are to: 1) evaluate whether removal of PR function alters murine susceptibility to carcinogen-induced mammary tumorigenesis at the morphological, histological, and molecular level; 2) determine whether PR function has a role in the development of hormone dependent mammary tumors exhibited by the Grunder mouse and define whether the PR has an involvement in the progression of these tumors to a hormone independent phenotype; and 3) to define the distinct effects of mammary epithelial and stromal derived PR populations on mammary development and tumorigenesis by using reciprocal mammary gland transplantation technology. Apart from advancing our current understanding of P's contribution to mammary tumorigenesis, information from these studies will aid in the design of effective strategies for breast cancer prevention and treatment as well as prompting a reevaluation of the current use of progestins in contraception and postmenopausal hormonal replacement therapies.